PROJECT SUMMARY/ABSTRACT Heart failure (HF) is characterized by markedly elevated levels of catecholamines that bind to adrenergic receptors (ARs) in the heart. The toxic effects of excessive beta (?)-AR stimulation are well described, and drugs that block ?-ARs are cornerstones of contemporary HF therapy. Cardiac alpha (?)1-ARs have received less attention, however data from cell and animal studies indicate that they protect against the development of HF. There are two ?1-AR subtypes in the heart: ?1A, and ?1B. The ?1B mediates cardiac hypertrophy induced by non-selective ?1-AR agonists like phenylephrine. Activation of the ?1A protects against cardiomyocyte death and increases contractility in the failing heart, though the mechanisms underlying these adaptive effects are poorly understood. We recently showed that an oral selective ?1A agonist drug, dabuzalgron, preserves ATP content and mitochondrial function in mouse HF models. These protective effects were abrogated by trametinib, a MEK-ERK1/2 inhibitor used to treat melanoma. Our recent preliminary data expand upon these novel findings by suggesting that ?1A activation may improve cardiac energetics through increased glucose utilization, coupling augmented glycolysis to glucose oxidation through enhanced oxidative phosphorylation. The overarching hypothesis of this proposal is that ?1A-ARs protect the failing heart through an ERK1/2-mediated increase in glucose metabolism that counteracts the deleterious metabolic effects of chronic ?1 hyperstimulation in HF. In Aim 1, we will use a cardiomyocyte-specific ?1A-AR knockout mouse in two mouse models of pathological hypertrophy and HF to confirm the requirement of cardiomyocyte ?1As for the cardioprotective effects of dabuzalgron. In Aim 2, we will find if ?1A-AR activation enhances glucose utilization to provide energy for the failing heart using transverse aortic constriction in vivo coupled with in vitro studies using selective pharmacology and gene silencing to identify key metabolic processes and signaling pathways affected by ?1A activation. Aim 3 will define the role of ERK1/2 activation in ?1A-mediated metabolic cardioprotection, using both trametinib and genetic modification of MEK-ERK axis to provide new insights on the role of ERK1/2 signaling in the regulation of glucose metabolism and mitochondrial function. Collectively the proposed experiments will expand our understanding of cardiac ?1A-ARs and challenge the prevailing paradigm that chronic catecholamine surge exerts uniformly deleterious effects in the failing heart.